They manage to completely eliminate pancreatic tumors in mice without the appearance of resistance.

We share the latest milestone from the Experimental Oncology Group at the CNIO, which has succeeded in eliminating pancreatic tumors in animal models using a triple combination therapy without generating resistance.

In Spain, more than 10.300 cases of pancreatic cancer, one of the most aggressive tumors, are diagnosed each year. Its detection at advanced stages, coupled with the lack of effective therapies, means that the five-year survival rate after diagnosis is less than 10%. But research It's taking off, and beginning to change the paradigm after decades of very little progress.

Mariano Barbacid, boss of Experimental Oncology Group Researchers from the Spanish National Cancer Research Centre (CNIO) have designed a therapy that completely and permanently eliminates pancreatic tumors in mice, without significant side effects. The study... publish in the magazine PNAS (Proceedings of the National Academy of Sciences), with Carmen Guerra as lead co-author and Vasiliki Liaki y Sara Barrambana as first authors.

“These studies open a path to designing new combination therapies that can improve survival for patients with pancreatic ductal adenocarcinoma [the most common pancreatic cancer],” the authors state in PNAS"These results set the course for developing new clinical trials."

Eliminate treatment resistance

The first drugs targeting molecular targets in pancreatic cancer were approved in 2021, after half a century without improvements over conventional chemotherapy. These new drugs block the action of KRAS, a gene mutated in 90% of people with pancreatic cancer; however, their effectiveness is modest because after a few months the tumor becomes resistant.

This problem of resistance to KRAS inhibitor drugs is what Barbacid's new study addresses, a pioneer in both KRAS research and the development of animal models for pancreatic cancer.

The CNIO group's strategy has been to block the action of the KRAS oncogene at three points, instead of just one—it's more difficult for a beam to break if it's fixed to the ceiling at three points, rather than just one. And, indeed, after genetically eliminating three molecules from the KRAS signaling pathway in mouse models, the tumors disappeared permanently.

Against three links in the chain

Applying the same strategy in patients involves searching for drugs that block the KRAS molecular pathway at the same three points. The team used a triple therapy, combining a KRAS inhibitor available for experimental studies (daraxonrasib); a drug approved for certain lung adenocarcinomas (afatinib); and a protein degrader (SD36).

The treatment was applied to three mouse models of pancreatic ductal adenocarcinoma, and in all of them it induced "a significant and lasting regression of these experimental tumors without causing significant toxicities," the authors write.

“This study describes a triple combination therapy that induces robust regression in experimental models of pancreatic ductal adenocarcinoma and prevents the development of resistance. This triple combination is well tolerated in mice,” they state. PNAS.

Towards a clinical trial, but not yet

Regarding the next steps, Barbacid explains that “it is important to understand that, although experimental results like those described here have never been obtained before, we are not yet in a position to carry out clinical trials with the triple therapy.”

“The path to optimizing the triple combination therapy described here for use in a clinical setting will not be easy,” it states. PNAS“(…) Despite current limitations, these results could open the door to new therapeutic options to improve the clinical outcome of patients with pancreatic ductal adenocarcinoma in the not too distant future.”

Source: SINC Agency